Lyme disease is the most commonly reported arthropod-borne infectious disease in the United States and Europe. The causative agent, B. burgdorferi, infects humans as accidental hosts via tick bites. Little is known about the importance of Borrelia components to infection or virulence. Our long-term goal is to elucidate virulence determinants and mechanisms of virulence as a prerequisite to developing therapeutic protocols for treatment of Lyme arthritis and prevention of the disease. The objective of this application is to determine the role of the Shk-Grr putative signaling system in the infectious cycle of B. burgdorferi. By generating the Shk-Grr-deficient mutants in infectious B. burgdorferi strains, our preliminary studies lead to the hypothesis that Shk-Grr is involved in spirochete adaptation in tick vectors. To test this hypothesis, we propose 1), to quantitatively determine the mutants' spirochete loads in various mouse organs as well as in ticks at various time points during feeding. Such studies should pinpoint the exact defect(s) of the mutant during its natural cycle; 2) to globally examine the influence of Shk-Grr-deficiency in gene expression by a microarray approach. Accomplishing the proposed aims will not only have an important impact in our understanding of the infectious cycle of B. burgdorferi, but also improve our understanding of vector- pathogen interaction and bacterial signal transduction in general. [unreadable] [unreadable] Accomplishing the specific aims outlined in this proposal will likely yield the discovery of a new regulatory pathway that is important for the infectious cycle of the Lyme disease pathogen. This will not only advance our understanding the molecular mechanism of the pathogenesis of Lyme disease, but also will lead to identification of new antimicrobial targets for disrupting the pathogen's transmission cycle. [unreadable] [unreadable] [unreadable] [unreadable]